Small Interfering RNAs: Patent Law’s Response to a Revolutionary Invention
Throughout the age of modern biology, science classes have taught the “central dogma” – genes are encoded on double stranded DNA, which is copied into single stranded “messenger” RNA (mRNA), and those mRNAs are then read to make proteins. Proteins were the “active” agents of the genes – they could act as enzymes to catalyze reactions necessary for basic cellular functions (generating energy, creating a new copy of the cell, or sending messages to other cells). Students were taught that RNA had a limited utility to the cell, primarily using the information encoded in genes to make proteins. This view was largely accurate, but failed to explain why so much of the genome was composed of “non-coding” DNA; that is to say, DNA that was not used to create mRNA. Biology students learned that the majority of these “non-coding” regions were “junk DNA” and lacked any specific purpose. This claim was recently disproved.
In 1996 the Nobel Prize was awarded to Professors Andrew Fire and Craig Mello, for their discovery of “small interfering RNAs” (siRNAs). They discovered that some non-coding regions of RNA played critical roles in the regulation of gene expression. Instead of coding for the creation of proteins, these RNAs acted as an off switch, de-activating mRNAs. Specifically, these short RNA sequences formed short double stranded regions (surprise! only DNA was supposed to be double-stranded) that were recognized by a protein complex and cut in half. Then the protein/RNA complex proceeded to do something truly shocking. Instead of dropping the cut (and now presumably useless) RNA strands, the protein complex retained one of the strands, and the two together romped around the cell binding to a specific target mRNA sequence and cutting them up. Far from useless – the non-coding RNA regions turned out to be very powerful regulators of gene expression. As a single mRNA may act as the template for hundreds or even thousands of proteins, a regulatory switch that can destroy all mRNAs from a specific gene can quickly and effectively terminate the effect of that gene within a cell (an activity termed RNA interference, or RNAi).
Beyond changing our fundamental understanding of genetics, RNAi presents the opportunity to develop powerful new medicines. From a legal perspective, the fascinating issue is not that RNAi has spawned numerous patents, but the scope claimed within those patents. Rather than develop and claim specific drug applications of siRNAs, the early patent battle has focused on the characteristics of “optimal” siRNAs. Specifically, different patents have been granted on specific sequences at each end of the siRNAs. These sequences do not directly govern targeting of siRNAs to specific gene products, but rather govern the degree of binding required to deactivate a particular target. Rather than patenting specific applications the parties are instead patenting a kind of “tool kit” that will have to be used by most, if not all specific applications. The obvious economic goal here is to harvest licensing fees from as many RNAi applications as possible.
Recently, the European Patent Office upheld Alnylam’s broad based patent on a broad range of uses for siRNAs (Alnylam holds a simlar patent in the U.S.). The patent was challenged by numerous parties including Sirna, a Merck subsidiary, and Silence Therapeutics. Silence’s role in this case is particularly ironic, given that Silence holds its own broad patent on an optimization of a specific end of the siRNA molecule. Intriguingly, Silence’s patent is up for reexamination here in the United States. In the coming years it will be interesting to follow how this battle plays out both in the courts and in commerce. RNAi is a fantastic discovery with the potential to facilitate new treatments for human diseases, and those who labored to discover and develop the technique deserve to be richly rewarded. However, this case also highlights the negative side of the current patent scheme: no single party is situated to take complete advantage of such a groundbreaking discovery. If one party abuses its monopoly power and refuses to grant reasonably priced licenses to other biotech inventors, then the patent system no longer effectively serves the public good.
Image By: Marjori A. Matzke, Antonius J. M. Matzke [CC-BY-2.5 (www.creativecommons.org/licenses/by/2.5)], via Wikimedia Commons